This proposal supports a randomized, double-blind, placebo-controlled, phase lIb trial of regadenoson for the treatment of acute vaso-occlusive episodes in children (> 14 years) and adults with sickle cell disease (SCD). Among African Americans, SCD is the most common genetic disorder affecting approximately 70,000 individuals in the United States. Acute exacerbation of chronic vaso-occlusion is the etiology for the two most common morbidities in SCD, pain and acute chest syndrome (ACS) episodes. The pathogenesis of vaso- occlusion is a multi-cellular process involving sickle and non-sickle erythrocytes, white blood cells, platelets, coagulation proteins and activated endothelium. Recently, a modified paradigm has emerged implicating ischemia/reperfusion (l/R) injury and, in particular, invariant NKT (iNKT) cells in the pathogenesis of vaso- occlusion. In murine models of SCD, treatment with regadenoson, an adenosine2A receptor agonist, inhibits iNKT cell activity thereby interrupting l/R injury and dampening the severity of pulmonary inflammation and edema. Our investigative team has an ongoing phase I clinical trial of infusional regadenoson in individuals with SCD. Preliminary data generated from this trial suggest that low-dose infusional regadenoson is safe and has biological activity, decreasing activation of INKT cells. Extending the findings in our phase I study, we have designed a phase lIb trial to examine the efficacy of regadenoson for the treatment of pain and ACS. In children (> 14 years) and adults with SCD, we will: 1) determine if infusional regadenoson is biochemically effective and reduces the severity of acute vaso-occlusive events (pain and ACS), 2) investigate the dose- and time-dependence of regadenoson to influence inflammatory biomarkers in blood, and 3) evaluate a portable magnetic resonance imaging instrument and contrast-enhanced ultrasonography, novel outcome measures to assess pulmonary interstitial edema and regional blood flow, respectively. In a multi-center trial at 9 institutions, we will treat 96 participants ith HbSS/HbS|3-thalassemia, ages 14 to 70 years, with a 48 hour infusion of regadenoson during a pain or ACS episode. Our primary outcome measure will be reduction in percentage of activated INKT cells as determined by NF-kB activation. We anticipate that administering infusional regadenoson during pain and ACS episodes will decease inflammation and improve clinical outcomes in SCD, and may lead to further investigations of this therapy in other refractory inflammatory states. RELEVANCE (See instructions): Sickle cell disease is a genetic condition of the blood. Pain and acute chest syndrome episodes are potentially lethal complications of sickle cell disease. We will study a drug called regadenoson in people with sickle cell disease to determine if it is an effective treatment for pain or acute chest syndrome episodes.